RU2791232C2 - Multi-block drug delivery devices and methods for drug delivery - Google Patents

Abstract

FIELD: medical equipment, implantable devices for drug delivery.

SUBSTANCE: devices comprise a body forming a tank, the first and second blocks located inside the tank. The first block contains the drug, and the second block contains a functional agent that facilitates drug release. Devices for intravesical drug delivery contain a body part containing a drug composition and a body part containing a filler, and are configured to release the drug in accordance with the first release profile and to release the filler in accordance with the second release profile.

EFFECT: inserting any of the devices into a patient and dispensing the drug from such device.

17 cl, 21 dwg

Description

FIELD OF TECHNOLOGY

[0001] This invention generally relates to controlled delivery of a drug to patients, in particular to medical devices for controlled release of a drug, including, without limitation, devices configured to be deployed in the bladder to release a drug into it.

BACKGROUND OF THE INVENTION

[0002] Various implantable drug delivery devices are known in the art. For example, US Patent Application Publication No. 2007/0202151 (Lee et al.) and US Patent Application Publication No. 2009/0149833 (Syma et al.) describe drug delivery devices for minimally invasive deployment and retention in a patient's body cavity, such like a bladder. These devices prevent excretion, for example, in response to efforts associated with urination. For example, the devices may comprise a retaining frame that may be configured to form a relatively small profile for deployment in the body, and upon implantation, said devices may take on a relatively expanded profile to facilitate retention. These devices can provide a controlled release of a drug in a predetermined manner over an extended period of time. In some embodiments, the devices comprise a permeable tube that defines a drug reservoir for receiving a drug and at least one opening for releasing that drug. Osmotic transfer or diffusion may be the primary mechanism by which a drug can be released from a reservoir. Drugs with high water solubility, such as lidocaine hydrochloride, can be released by osmotic pressure at treatment-useful rates over an extended period of time. In other embodiments, the device may be configured to release lower solubility drugs or other drugs primarily or only by diffusion.

[0003] However, it may be necessary to provide improved devices and systems for drug delivery. For example, it may be desirable to provide devices, systems, and methods in which relatively lower solubility drugs can be released at treatment-useful rates by means of osmotic pressure over an extended period of time. It may also be desirable to provide implantable drug delivery devices and systems capable of delivering a variety of different active agents at a chosen kinetic release profile, and to provide additional technologies, structures and/or formulations to improve in vivo drug release management. ), for example, from a device deployed in the bladder.

DISCLOSURE OF THE INVENTION

[0004] In one aspect, an implantable drug delivery device is provided, comprising a body forming a reservoir, a first block located in the reservoir, and a second block located in a position different from the position of the first block. The first block contains the drug, and the second block contains a functional agent that, in vivo, facilitates the release of the drug from the housing.

[0005] In another aspect, an intravesical drug delivery device is provided, comprising a first housing portion loaded with a drug formulation that contains a drug and a second housing portion loaded with a vehicle. The device is configured to release the drug according to the first release profile and to release the excipient according to the second release profile different from the first release profile.

[0006] In yet another aspect, a method of administering a drug to a patient is provided, comprising administering to the patient a drug delivery device as disclosed herein and releasing the drug from the administered device.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 shows a sectional view of an embodiment of a known drug delivery device.

[0008] FIG. 2 shows a sectional view of one embodiment of a multi-unit drug delivery device.

[0009] FIG. 3 shows a sectional view of another embodiment of a multi-unit drug delivery device.

[00010] FIG. 4 is a sectional view of another embodiment of a multi-unit drug delivery device.

[00011] FIG. 5 shows a sectional view of one embodiment of a multi-unit drug delivery device.

[00012] FIG. 6 is a perspective view of a portion of the multi-unit drug delivery device of FIG. 5.

[00013] FIG. 7 shows an example configuration of a drug delivery device having one or more drug body parts.

[00014] FIG. 8 is a plan view of an embodiment of a drug delivery device having more than one drug housing part.

[00015] FIG. 9 is a graph illustrating the percentage release of drug over time from a single tablet drug delivery device as well as from a dual tablet drug delivery device.

[00016] FIG. 10 is a graph illustrating drug release rates over time from a single tablet drug delivery device as well as from a dual tablet drug delivery device.

[00017] FIG. 11 is a graph illustrating the drug delivery percentage over time from a drug delivery device having a laser-shaped opening and a drug delivery device having a separating hole.

[00018] FIG. 12 is a graph illustrating a drug delivery rate over time from a drug delivery device having a laser-shaped hole and a drug delivery device having a separating hole.

[00019] FIG. 13 is a graph illustrating the percentage release of drug over time from a drug delivery device containing a powdered drug and an osmotic tablet and from a drug delivery device containing a drug tablet and an osmotic tablet.

[00020] FIG. 14 is a graph illustrating the rate of drug release over time from a drug delivery device containing a powdered drug and an osmotic tablet and from a drug delivery device containing a drug tablet and an osmotic tablet.

[00021] FIG. 15A-15B are perspective and sectional views, respectively, of one embodiment of a drug delivery device housing.

[00022] FIG. 16 is a cross-sectional view of one embodiment of a drug delivery device in which the reservoir contains a channel for a flow modulator.

[00023] FIG. 17 is a sectional view of one embodiment of a multi-unit drug delivery device.

[00024] FIG. 18 is a sectional view of one embodiment of a multi-unit drug delivery device.

[00025] FIG. 19 is a graph illustrating the amount of drug released over time from a drug delivery device having different body wall thickness and hardness.

[00026] FIG. 20 is a graph illustrating the amount of drug released over time from a drug delivery device having different body wall thickness and hardness.

[00027] FIG. 21 is a graph illustrating the amount of drug released over time from a drug delivery device having a body coated with different lengths.

IMPLEMENTATION OF THE INVENTION

[00028] The devices are configured to be inserted into a patient's body cavity to deliver medication locally or zonal around the implantation site. In one embodiment, the devices comprise drug blocks and separate blocks for a second agent that accelerates the release of the drug. In vitro examples show improvements in short and long term drug release profiles compared to comparable single-unit devices. In addition, these devices advantageously allow low solubility drugs to be delivered to patients via osmotic release devices. This is particularly useful for drugs that are difficult to convert to higher solubility forms. In addition, osmotic release is generally preferred over diffusion-based release when drug solubility is highly dependent on the pH of the release medium and it is necessary to reduce the pH dependence of drug release.

[00029] For the purposes of the present invention, the term "implantation site" generally refers to a location within the body of a human patient or other living organism. The implantation site can be any genitourinary site such as the bladder, urethra, ureters, kidneys, prostate, seminal vesicles, ejaculatory duct, vas deferens, vagina, uterus, fallopian tubes, ovaries, or any other site, among other sites, within the urological or reproductive system body. In specific embodiments, the site of implantation is the bladder.

[00030] In particular embodiments, the devices are configured to be deployed through natural orifices and body cavities in minimally invasive deployment procedures. For example, the devices may have a deployment form suitable for deployment through a natural body cavity. The devices are also configured to be retained within the body after implantation, for example by achieving a retaining shape after implantation or by securing them within the body. In particular embodiments, the devices can be deployed through the urethra into the bladder and, upon implantation, can overcome voiding forces to be retained in the bladder.

[00031] Once implanted, the devices may release one or more drugs for an extended period of time. The drug can be released through an orifice in the device by osmotic pumping, diffusing across the surface of the device, diffusing from an orifice in the device, or a combination of the two. The release of the medicinal product may be continuous and in accordance with a predetermined release profile.

[00032] In specific embodiments, devices are loaded with one or more drug and functional agent units. As used in this application, the term "functional agent" refers to agents or excipients that in vivo facilitate the controlled release of a drug from a device. For example, functional agents may contain osmotic agents, drug dissolving agents, drug stabilizing agents, permeation enhancing agents, or a combination thereof. The functional agent may be selected based on the drug or drugs to be delivered or to be delivered from the device. For example, the drug to be delivered may be a low solubility drug and the functional agent may contain an osmotic agent to facilitate in vivo osmotic release of the drug.

[00033] As used in this application, the term "low solubility" refers to a drug having a solubility of from about 0.001 mg/ml to 10 mg/ml at a water temperature of 37°C. As used in this application, the term "high solubility" refers to a drug having a solubility above about 10 mg/ml of water at a temperature of 37°C. The solubility of a drug may depend at least in part on its form. For example, a drug in the form of a water-soluble salt may have high solubility, while the same drug in the form of a base may have low solubility.

[00034] In conventional drug delivery devices, drugs with high solubility in general can be made suitable for release according to an induced osmotic pressure gradient, while drugs with low solubility can be made suitable for release by diffusion through wall or passageway in the drug housing. The devices disclosed herein are capable of delivering a variety of different drugs through various release patterns and release kinetic profiles, and with the ability to provide additional techniques, structures, and/or formulations to improve in vivo drug release management.

[00035] Regardless of whether the selected drug has high or low solubility, it must be delivered (i.e., released from the delivery device) at a rate effective for treatment, which may require the addition of one or more functional agents (for example, an osmotic agent to enhance water flow, a solubilizing or solubilizing agent, a pH adjusting agent, or an agent to improve stability). In general, the combination of the solubility of the selected drug in the presence or absence of functional agents, if present, and the osmotic flow of water will determine the rate and duration of release, and such a combination can be made for a rate and duration that is in the range of values effective for treatment.

[00036] The devices and methods disclosed in this application are based on the devices and methods described in U.S. Patent Application Publications No. 2010/0331770 (Lee et al.), No. 2011/0152839 (Saima et al.) and No. 2012/0203203 (Lee and others), which are incorporated herein by reference.

[00037] I. Implantable drug delivery devices

[00038] Embodiments of the implantable drug delivery devices disclosed herein generally comprise a housing forming a reservoir, first and second units contained within the reservoir. For example, the body may be elongated, the annular tube and the reservoir may be the cavity of the annular tube.

[00039] The first block or first blocks contain or contain the drug or active pharmaceutical ingredient to be delivered to the patient, and the second block or second blocks contain or contain a functional agent that naturally (in vivo) facilitates the release of the drug from the housing . The first and second blocks are located at different positions within the tank. That is, the first and second blocks are made different and separated from each other. For example, the first and second blocks may be solid tablets that are adjacent in a reservoir.

[00040] Referring to FIG. 1, a typical drug delivery device 100 comprises multiple identical tablets 102 arranged in a reservoir 104 (for clarity and ease of comparison with other embodiments shown, device 100 is shown in linear form, which may be helpful during the process of inserting the device into a patient). Tablets 102 contain the drug to be delivered and, if necessary, one or more excipients. After implantation, device 100 releases the drug through opening 106 in device 100 by osmotic pumping. However, the release mode and kinetics of the drug are limited by the composition of the tablet, as well as the characteristics of the body construction materials.

[00041] One embodiment of the present invention is shown in FIG. 2. An implantable drug delivery device 200 includes a housing 208 that defines a reservoir 204. second blocks 210 which contain the functional agent, said first blocks and said second blocks being located in the tank 204. The first block 202 and the second block 210 are located at different positions within the tank 204. This design, in particular, may be preferred, as described in detail Further.

[00042] The structure of the device, in combination with drug and functional agent formulations, can be configured to release the drug and functional agent by osmosis and/or diffusion.

[00043] FIG. 2 shows a device 200 that is configured to operate as an osmosis pump. The device body 208 includes a wall that is easily permeable to water, but impervious to a drug to be delivered, as well as a drug that cannot easily diffuse through the wall of the body 208. That is, the water-permeable portion can be made substantially impermeable. for a drug in aqueous solution. The permeable portion of the wall may form at least a portion of the reservoir 204. Upon deployment of the device to the patient, water (or urine, if present in the bladder) permeates the wall, enters the reservoir 204, and dissolves the first block 202 and/or the second block 210. Alternatively, In a variant, in combination with the water-permeable part of the wall, the body may contain at least one opening, made with the possibility of letting fluid into the reservoir in natural conditions (in vivo). For example, the housing and/or any water-permeable wall portions may be made of silicone, TPU, ethylene vinyl acetate (EVA), or a combination thereof.

[00044] The introduction of some of the dissolving fluid into the reservoir prior to implantation may, if necessary, accelerate the hydration process of the tablets or formulations contained therein. In an embodiment, the device is configured to provide at least a portion of the aqueous fluid needed to dissolve the functional agent or drug prior to implantation. For example, fluid may be delivered to the reservoir of the device via a needle and syringe. In one embodiment, the housing portion contains a low hardness material suitable for penetration by a needle or other instrument. For example, the body may comprise an axial spacer having a portion of low hardness material surrounded by a portion of high hardness material. In another example, the housing may include a unidirectional sealing element.

[00045] After implantation, the osmotic pressure gradient between the inside and outside of the device body increases, and after sufficient pressure is reached, the dissolved drug is released from the reservoir 204 through at least one drug outlet 206, which communicates with the reservoir 204 through a fluid with at a controlled rate set by the osmotic pressure in reservoir 204. This mode of release may be referred to in this application as "osmotic release" or "osmotic pumping."

[00046] Referring to FIG. 2, the medicament outlet 206 may be provided in an end cap located at the end of the hollow body 208. Such end caps are also referred to as "split holes" described in greater detail in International Application No. PCT/US14/20703, filed March 5, 2014. year and which is incorporated into this application by reference. In FIG. 3 shows another embodiment of an osmotic device 300 that includes a drug outlet 306 in the side wall of the housing 308, said hole being configured to allow the dissolved drug to pass through.

[00047] Referring to FIG. 17, the drug delivery device 1700 may include a containment plug 1707 at the end of the hollow body 1708. In this embodiment, the containment plug 1707 controls the release of the drug through an intermediate substance of one or more microchannels between the elastic part of the body 1708 and the containment plug. For example, osmotic tablets 1710 of a drug tablet 1702 may be contained in a reservoir 1704 that is delimited by a sealed end 1713 and a containment plug 1707 that can be held in place by an adhesive 1709 that secures one portion of the containment plug to the body without interfering with the intermediate. microchannels located between the other part of the containment plug and the body (for example, in the area remote from the adhesive). Such containment plug/microchannels are described in more detail in International Application No. PCT/US14/28317, filed March 14, 2014, and incorporated herein by reference.

[00048] In particular embodiments, the first block, ie. block for the drug, located closer to the second block, i.e. block with a functional agent, to the drug outlet, the drug-permeable part of the wall, or to the containment plug. This design has been shown to be particularly advantageous in terms of achieving a therapeutically effective drug release rate for specific drugs, such as drugs of low solubility.

[00049] When osmotic release is a desired drug release mode, the functional agent in the second block may contain an osmotic agent that facilitates osmotic release of the drug. For example, the osmotic agent may have a higher solubility than the drug, so that the osmotic agent accelerates the dissolution and/or subsequent release of the drug. This advantageously allows delivery of low solubility drugs or other drugs typically delivered from osmotic delivery devices by diffusion only.

[00050] The device 200 may exhibit an administration period during which a sufficient volume of functional agent and/or drug is dissolved to achieve an osmotic pressure gradient. Therefore, the device 200 may exhibit a zero order release rate for an extended period of time, followed by a decrease in the non-zero order release rate over the decay period. The desired delivery rate can be achieved by controlling or selecting various device parameters including, but not limited to, surface area and water-permeable wall thickness, water-permeability of the material used to form the wall, shape, size, number and arrangement of holes 206, drug dissolution profiles. agent and functional agent.

[00051] The devices described in this application can also be configured to release the drug by diffusion alone or in combination with osmotic release. The device may be configured to pass the dissolved drug through a portion of its body or through one or more holes located therein.

[00052] In particular embodiments, the water-permeable body wall portion is also permeable to the drug in aqueous solution, such that the dissolved drug is released through the wall portion, referred to herein as "diffusion through the wall." After the device is implanted, water or urine permeates through the wall, enters the reservoir and dissolves the functional agent and/or drug. The drug then diffuses directly through the wall at a controlled rate due to the drug concentration gradient between the inside and outside of the device. For example, the body and/or any water or drug permeable wall portions may be made of silicone, TPU, ethylene vinyl acetate (EVA), or a combination thereof.

[00053] In particular embodiments, the housing does not have an outlet and is configured to discharge medication through at least one drug-permeable wall defining the reservoir. For example, the drug-permeable wall may comprise a disc fixed in the cavity of the tube at or near the end of the tube, optionally positioned between the inner washer and the outer washer. Drug-permeable walls are described in more detail in US Patent Application No. 14/216,112, filed March 17, 2014, which is incorporated herein by reference. In other embodiments, the drug-pervious wall is part of a side wall of the hollow body or part of an end plug located at the end of the hollow body.

[00054] Alternatively, in which, in combination with the water-permeable wall portion, the housing may include at least one opening configured to admit fluid through it into the reservoir under natural conditions (in vivo). The housing may also contain one or more openings or permeable pores configured to allow the dissolved drug to pass through.

[00055] As described above, the device may also be configured to receive at least a portion of the water or fluid necessary to dissolve the functional agent or drug prior to implantation, such as through a needle and syringe.

[00056] The device may exhibit a zero order release rate for an extended period of time followed by a decrease in the non-zero order release rate over a period of decay. Zero-order release can start relatively quickly because the drug can immediately be allowed to diffuse through the housing wall after it has been dissolved. The rate of delivery depends on the surface area and wall thickness, the water and drug permeability of the material used to form the wall, the charge or particle size of the drug, the dissolution profile of the drug, and among other factors from the functional agent. In embodiments in which the drug is released through one or more orifices or permeable pores, multiple orifices or permeable pores or combinations thereof may be used, which may also affect the overall release rate attributed to diffusion.

[00057] In particular embodiments, the first and/or second block is in the form of a hard tablet. For example, according to FIG. 4, the first block 402 is in powder form, while the second block 410 is in the form of solid tablets. In other implementations, as shown in FIG. 2 and 3, the first and second blocks are made in the form of solid tablets. In specific embodiments, hard tablets are in the form of "mini-tablets" as described in US Pat. No. 8,343,516 (Daniel et al.). In the embodiments of FIG. 5, the device 500 includes a plurality of first hard tablet blocks 502 and a plurality of second hard tablet blocks 510.

[00058] In specific embodiments, each drug block tablet contains a relatively high weight fraction of drug and a relatively low weight fraction of excipient. For example, each drug tablet may contain more than 50% drug by weight, allowing a relatively small device to be loaded with an effective amount of drug for treatment. The release rate of the drug from the device can be controlled advantageously by combining the properties of the functional agent and the drug housing, and changed by adjusting the properties of the housing, such as its thickness and permeability, and composition with the functional agent.

[00059] The implantable device can be configured to be deployed and held in a body part such as the bladder. The device can be made flexible so that the device can be deformed for its insertion, and after implantation, the device can resist the release in response to the efforts of urination or other forces. In one embodiment, the drug-loaded device is flexible or deformable, regardless of whether it is loaded with a solid drug block and/or tablets of a functional agent block, since each drug block is movable with respect to adjacent blocks. for a medicinal product. In particular, gaps or gaps between the individual drug blocks can form elevations that allow the device to deform while allowing the individual blocks to maintain their solid shape, as described in US Patent Application Publication No. 2010/0331770 (Lee et al.)

[00060] The useful masses of some solid drug and/or functional agent are generally flexible, including powder blocks 402 as shown in FIG. 4, or payloads formed from individual solid tablets 602, 610 that can move relative to each other as shown in FIG. 6.

[00061] As described above, the body of the device may be formed from at least a partially water-permeable material. For example, the housing may be formed from a water-permeable material that allows water to diffuse into the medicament housing along its entire length, a portion thereof, or at one or both ends of the device.

[00062] In a specific embodiment, the body is made in the form of one or more elongated annular tubes containing two wall parts, one of which is made permeable to water and the other is impervious to water. In FIG. 15A-B show one embodiment of an annular tube. In the present invention, the annular tube 1500 includes a water-tight wall portion 1510 and a water-permeable wall portion 1520. Upon administration to a patient, water enters cavity 1530 through wall portion 1520 where it will contact the solid drug and/or functional agent payloads located in the cavity and increase the solubility of the solid drug and/or functional agent payloads (not shown) . This structure can be formed by, for example, co-extrusion. The relative proportions of the two wall parts can be selected based, for example, on the required rate (and thus surface area available for) water penetration and on the mechanical properties, for example, to ensure that the device has the elasticity or hardness values required for transurethral insertion, retention and stability of the bladder, as described, for example, in US Patent Application Publication No. 2011/0152839 (Syma et al.).

[00063] Referring to FIG. 18, the drug delivery device 1800 may include a region of a water-impervious cover 1809 located along at least a portion of the hollow body 1808. That is, the water-impermeable wall portion may be formed by covering the body with a waterproof material. For example, osmotic tablets 1810 and drug tablets 1802 may be contained in a reservoir 1804 that is defined by a sealed end 1813 and an outlet plug 1806. Upon administration to a patient, water enters the reservoir 1804 through the water-permeable housing 1808 (but not through the water-impermeable region 1809), where it contacts the functional agent or drug tablet payloads located in the housing and enhances their solubility. The water-impervious region provides controlled dissolution and release of the drug. In particular, the body coating may be useful in osmotic release devices in which the body material is made permeable to the drug.

[00064] For example, the area of the waterproof coating may extend along the body for a length of 4 cm to 11 cm, for example, for a length of 6.5 cm. functional agent tablets and 2 to 4.5 cm drug tablets, and also contains an impermeable coating area extending along the body for a length of 4 cm to 11 cm. frame.

[00065] As described above, the wall of the device body may have one or more passages through its surface to provide a path for the flow of water and/or drug from the reservoir. In some embodiments, the wall may be porous, which means that the wall may have one or more transmissive pores formed therein. In other embodiments, the wall may have a defined opening completely formed in the wall, such as by drilling, perforating, or molding. The hole may have a round or other shape. The opening may have a straight or tapered sidewall extending through the wall described above.

[00066] In some embodiments, the wall is made of a resilient, biocompatible polymeric material. The material can be made non-absorbable or absorbable. Exemplary non-resorbable materials comprise synthetic polymers selected from poly(ethers), poly(acrylates), poly(methacrylates), poly(vinyl pyrrolidones), poly(vinyl acetates), poly(urethanes), cellulose, cellulose acetates, poly(siloxanes), poly (ethylene), poly(tetrafluoroethylene), and other fluorine-containing polymers and poly(siloxanes). Exemplary resorbable materials, especially biodegradable or biodegradable polymers, comprise synthetic polymers selected from poly(amides), poly(ethers), poly(amide esters), poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudopoly(amino acids). ), poly(glycerol sebacate), poly(lactic acids), poly(glycolic acids), poly(lactic glycolic acids), poly(caprolactones), poly(caprolactone) derivatives (PC), poly(amide esters) (PEA ) and poly(octane-diol citrate) (ROS) based on amino alcohol and other curable self-absorbable elastomers. Polycaprolactone (PC) based polymers may require additional crosslinking agents such as lysine diisocyanate or 2,2-bis(ε-caprolacton-4-yl)propane to acquire elastomeric characteristics. Copolymers, mixtures and combinations of the above materials can also be used.

[00067] In particular embodiments, the housing may be formed from a water-permeable and elastic material. Silicone is one exemplary polymeric material that is elastic and can serve as a water-permeable membrane when formed as a thin wall, with permeability determined at least in part by wall thickness. For example, a thin wall of silicone may have a thickness in the range of about 100 mm to about 1000 mm, but other wall thicknesses may be used. In addition, a thin wall of silicone may be permeable to certain drugs, depending on, for example, the porosity of the wall, the drug's molecular size, its molecular weight, or its charge.

[00068] The size of the housing, including wall thickness, may be selected based on the volume of drug and functional agent formulations to be contained, the desired rate of drug delivery from the tube, the intended implantation site of the device within the body, the required mechanical integrity of the device , the required rate of release or permeability to water and urine, the required time of administration before the onset of the initial release, and, among other things, based on the desired method or route of administration to the body. The thickness of the tube wall can be determined based on the mechanical properties and the water-permeable material of the tube, as a tube wall that is too thin may not have sufficient mechanical integrity, while a tube wall that is too thick may result in an undesirably long insertion time for initial drug release. means from the device and/or may not have sufficient elasticity to allow delivery through the urethra or other narrow body cavity.

[00069] For example, the housing may be elongated, with an annular tube having an inner diameter of 2 mm to 5 mm. The first and second blocks may be hard tablets having a diameter substantially the same as the inside diameter of the elongated annular tube. One or more tablets of the first block may fill the length of the tube cavity by 1 cm - 3 cm, and one or more tablets of the second block may fill the length of the cavity of the tube by 10 cm - 15 cm. In one embodiment, the ratio of the volumes of the first block or first blocks and the second block or second blocks is from about 0.05 to 0.5. Other lengths and ratios of useful weight of the tablet are also possible.

[00070] For example, the housing may be an elongated annular tube having a wall thickness of 0.1 mm to 0.4 mm, such as a wall thickness of 0.2 mm. The body material can be selected such that the body has a hardness of 25 A to 80 A, such as 25 A, 50 A, 65 A, 70 A, or 80 units on the A scale.

[00071] In particular embodiments, the device is configured to resiliently deform between a relatively straight shape suitable for insertion through the urethra into the patient's bladder and a retention shape suitable for holding the device within the bladder. For example, the device may include a retaining frame cavity in which the retaining frame is located. The retaining frame may be made of superelastic alloy or other elastic wire as described in US Patent Application Publication No. 2010/0331770 (Lee et al.), which is incorporated herein by reference.

[00072] FIG. 5 shows an exemplary embodiment in which a device 500 includes a housing 508 that houses a first block 502 and a second block 510, as well as a retention frame 512. The medication housing 508 is axially aligned with the retention frame 512 and is made of a flexible material that provides the ability to move the device 500 between the holding mold shown in FIG. 5 and a flattened unfolding shape such as shown in FIG. 3. "Holding shape" generally means any shape suitable for holding the device at the intended implantation site, including but not limited to the pretzel shape shown in FIG. 5, i.e., designed to be suitable for holding the device in the bladder, while "deployment shape" generally means any shape suitable for deployment in the body of a drug delivery device having the linear or elongated shape shown in FIG. 3, that is, made suitable for deployment of the device through the working channel of a deployment tool placed in the urethra or other natural cavity. In one embodiment, the device is configured to spontaneously assume a shape having interconnected and overlapping pairs of rings in the absence of a compressive load received, for example, during advancement of the device through the deployment mold and/or through the deployment tool.

[00073] Referring to FIG. 16, in particular embodiments, reservoir 1604 of device 1600 includes a flow modulator conduit 1642 located between first block 1602 and second block 1610. For example, the flow modulator conduit may be a passage having a diameter smaller than that of the reservoir. The channel for the flow modulator may serve to restrict flow between the channels (ie reservoir regions) and thus slow the release of the drug from the housing by limiting its ability to contact the drug. In particular embodiments, the device may comprise more than one channel for a flow modulator to subsequently control the rate of drug release from the device.

[00074] In specific embodiments, the drug delivery device comprises a first body part loaded with a drug composition and a second body part loaded with a filler, and is also configured to release the drug in accordance with the first release profile and is configured to release filler according to a second release profile different from the first release profile. Body parts can achieve different release rates in different configurations by accommodating different compositions or by using different release mechanisms or by combining them, inter alia. The housing parts are made with the possibility of their combination to achieve the required drug release profile. For example, the excipient may be a functional agent that is configured to facilitate the release and/or delivery of a drug, such as a drug dissolving agent, a drug stabilizing agent, or a permeation enhancing agent. The drug and/or excipient formulation may be in the form of one or more tablets.

[00075] For example, the device may include body parts that exhibit different insertion times or delay times before initial release occurs, and that release drug and excipient at different rates or according to different release curves after release occurs, or that release drug and filler for various periods of time before the usable masses are substantially used up, among others, or a combination of the above. The various body parts are designed to be combined as a whole to achieve a desired release profile from a drug delivery device, such as a release profile that shows a relatively short initial delay time and then shows continuous release at a relatively constant rate over an extended period of time. .

[00076] For example, the drug and excipient can be released by osmotic pumping or diffusion, as described above, or by a combination of both. In specific embodiments, the drug is released from the first housing part, through an opening in the first housing part, preferably by osmotic pressure, and the excipient is released from the second housing part by diffusion. In another embodiment, the drug is released from the first housing part by diffusion through a drug-permeable wall in the first housing part, and the excipient is released from the second housing part, through an opening in the second housing part, preferably by osmotic pressure.

[00077] In specific embodiments, the drug delivery device comprises at least two separate or separate body parts associated with a single holding part. The body parts can be made as separate tank bodies, each of which is associated with the holding part, or as separate areas located inside a single body, that is, associated with the holding part. In FIG. 7 shows illustrative body parts with separate reservoir bodies from Examples A-C. FIG. 7 also shows exemplary housing portions which are separate areas within the single housing of Examples D through F. FIG. 7 also shows parts of the housing from Examples G to I, which may be configured depending on materials and construction.

[00078] FIG. 8 shows a plan view of another embodiment of a drug delivery device 800, the body of which is divided into several separate parts. Three body parts 802, 804 and 806 are shown, and any other numbers may be used. Each housing part is formed by a housing wall part and at least one spacer structure 808 which separates the housing part from an adjacent housing part. The spacer structure 808 may be a plug inserted into the housing, such as a cylinder, sphere, or disk, among others, said plug being held in place by its size or by an adhesive. The spacer structure 808 may also be part of a housing formed directly in this housing, for example, by molding. For example, the gratings shown in Examples D-E of FIG. 7 are spacer structures that separate the body parts along the length of the device.

[00079] A device with at least two separate body parts can be configured to control the release of a payload of at least one drug, excipient, or functional agent from an appropriate number of reservoirs. The two different parts may have the same or different configurations, for example one of the configurations described above with reference to FIG. 1-6, or a combination thereof. Configurations of drug delivery devices having two different drug parts are further described in US Patent Application Publication No. 2011/0060309 (Li et al.).

[00080] II. Uses and Applications of Implantable Drug Delivery Devices

[00081] The implantable drug delivery devices described herein can be used in many different medical fields, in particular in the therapeutic and prophylactic treatment of patients. In specific embodiments, the device is configured to deliver a drug such as lidocaine, gemcitabine, docetaxel, carboplatin, cisplatin, oxyplatin, trospium, tolterodine, or mitomycin C.

[00082] In some embodiments, the devices provide pain relief to the patient. Many different anesthetic agents, analgesic agents, and combinations thereof may be used. In embodiments, the device delivers one or more local anesthetic agents. The local anesthetic agent may be an analogue of cocaine. In specific embodiments, the local anesthetic agent is an aminoamide, an aminoester, or combinations thereof. Illustrative examples of aminoamides or amide class anesthetics include articaine, bupivacaine, sarticaine, cinchocaine, local anesthetic, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine. Illustrative examples of amino esters or ester class anesthetics include amylocaine, benzocaine, butacaine, chlorprocaine, cocaine, cyclomethicone, dimethocaine, hexylcaine, larocaine, meprilcaine, metabutoxycaine, orthocaine, piperocaine, procaine, proparacaine, propoxycaine, proxymethacin, rhizocaine, and tetracarisocaine. These local anesthetics are generally weak bases and can be converted to a salt, such as the hydrochloride salt, to dissolve in water, although alkaline or hydrated form anesthetics can be used. Other anesthetics such as lontocaine may also be used. The drug may also be an antimuscarinic compound such as oxybutynin or propiverine which exhibits an anesthetic effect. The drug may also contain other drugs described in this application, alone or in combination with a local anesthetic agent.

[00083] In specific embodiments, the analgesic agent contains an opioid. Illustrative examples of opioid agonists include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, besitramide, buprenorphine, butorphanol, clonitazen, codeine, desomorphine, dextromoramide, dezocin, diapromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutyratene, eptazocine, eptoheptazine, ethylmethylthiambutene, ethylforphine, etonitazene fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levofenailmorphan, lofentanil, meperedine, meptazinol, metazocin, methadone, metopone, morphine, mirofin, nalbuphenorphanic, narcein, norcein , normetadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, pantopon, pentazocine, fenadoxone, phenomorphone, phenazocine, fenoperidine, piminodine, pyrithramide, proheptazine, promedol, properidin, propyram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts and mixtures of them. Other opioid drugs such as mu, kappa, delta and nociceptive opioid receptor agonists are contemplated.

[00084] Illustrative examples of other suitable pain relieving agents include salicylic alcohol, phenazopyridine hydrochloride, acytaminophen, acetylsalicylic acid, flufenisal, ibuprofen, indoprofen, indomethacin, and naproxen.

[00085] In embodiments, the drug delivery device is used to treat inflammatory conditions such as interstitial cystitis, chemical cystitis, radiation cystitis, radiation and chemotherapy-induced hemorrhagic cystitis, ketamine-induced cystitis (or ketamine bladder syndrome), irritable bowel syndrome. bladder, prostatitis, urethritis, postoperative pain and kidney stones. Non-limiting examples of specific drugs for such conditions include lidocaine, immunosuppressive agents (eg, tacrolimus, liposomal tacrolimus), glycosaminoglycans (eg, chondroitin sulfate, sulodexide), pentosan polysulfate sodium (PPS), dimethyl sulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate, ketorolac, or a combination thereof. For kidney stones, drug(s) may be selected to treat pain and/or to accelerate the breakdown of the stones.

[00086] In some embodiments, a drug delivery device is used in conjunction with placement of a urethral stent, for example, to treat pain, urinary urgency, or frequent urination caused by placement of a urethral stent. Non-limiting examples of specific drugs for such treatment include antimuscarinics, α-blockers, narcotics, and phenazopyridine, among others.

[00087] The drug delivery device can be used, for example, to treat urinary incontinence, urinary frequency or urinary urgency, including urgency and neurogenic incontinence, as well as trigonitis. Drugs that can be used include anticholinergic agents, antispasmodic agents, antimuscarinic agents, β-2 agonists, alpha-adrenergics, anticonvulsants, norepinephrine uptake inhibitors, serotonin uptake inhibitors, calcium channel blockers, potassium channel disintegrant, and muscle relaxants. Illustrative examples of suitable drugs for the treatment of incontinence include oxybutynin, oxybutynin S, emepronium, verapamil, imipramine, flavoxate, atropine, propanteline, tolterodine, rociverine, clenbuterol, darifenacin, terodiline, trospium, hyoscyamine, propiverine, desmopressin, vamicamide, clydium bromide, hydrochloric acid. dicyclomine acid, amino alcohol ester glycopyrrolate, ipratropium bromide, mepenzolate bromide, methoscopolamine bromide, scopolamine hydrobromide, iotropium bromide, fesoterodine fumaric acid, YM-46303 (Yamanouchi Co., Japan), lanperisone (Nippon Kayaku Co., Japan), inaperisone, NS-21 (Nippon Shinyaku Orion, Formenti, Japan/Italy), NC-1800 (Nippon Chemiphar Co., Japan), ZD-6169 (Zeneca Co., UK) ) and stylonium iodide.

[00088] In other embodiments, the drug delivery device is used to treat urinary tract cancer, such as bladder cancer or prostate cancer. Drugs that may be used include antiproliferative agents, cytotoxic agents, chemotherapeutic agents, or a combination thereof. Illustrative examples of drugs that may be suitable for the treatment of urinary tract cancer include Bacillus Calmette-Guérin (BCG) vaccine, docetaxel, oxyplatin, carboplatin, cisplatin, doxorubicin, valrubicin, gemcitabine, mycobacterial cell wall DNA complex (MCC), methotrexate, vinblastine, thiotepa, mitomycin, fluorouracil, leuprolide, diethylstilbestrol, estramustine, megestrol acetate, cyproterone, flutamide, selective estrogen receptor modulators (i.e. selective estrogen receptor modulator (SERM) such as tamoxifen), butolotoxins, histone deacetylase inhibitors (eg, hydroxamic acid suberoylanilide) and cyclophosphamide. The drug may be a biologic and may contain a monoclonal antibody, a trinitrofluorenone (TNF) inhibitor, an anti-leukin, or the like. The drug may also be an immunomodulator, such as a TLR agonist containing imiquimod, or another TLR7 agonist. The drug may also be a kinase inhibitor, such as a fibroblast growth factor receptor 3 (FGFR3) selective tyrosine kinase inhibitor, a phosphatidylinositol 3-kinase (PI3K) inhibitor, or a mitogen-activated protein kinase (MAPK) inhibitor, among others, or combinations thereof. Drug treatment can be combined with conventional radiation or surgical treatment directed at the cancerous tissue.

[00089] In still other embodiments, the device is used to treat infections of the bladder, prostate, and urethra. Antibiotics, antibacterial, antifungal, antiprotozoal, antiseptic, antiviral, and other anti-infective agents may be administered to treat such infections.

Illustrative examples of drugs for the treatment of infections include mitomycin, ciprofloxacin, norfloxacin, ofloxacin, methanamine, nitrofurantoin, ampicillin, amoxicillin, nafcillin, trimethoprim, trimethoprim-sulfamethoxazole sulfonamides, erythromycin, doxiclin, metronidazole, tetracycline, kanamycin, penicillins, cephalosporins, and aminoglycosides.

[00090] In other embodiments, the device is used to treat fibrosis of the genitourinary site, such as the bladder or uterus. Illustrative examples of drugs for the treatment of fibromas include pentoxifylline (a xanthine analog), trinitrofluorenone (TNF) anti-inhibitor, agents to eliminate transforming growth factor (TGF), gonadotropin-releasing hormone (GnRH) analogs, exogenous progestins, antiprogestins, selective estrogen receptor modulators, danazol and non-steroidal anti-inflammatory drugs (NS AID).

[00091] The drug delivery device can also be used to treat neurogenic bladder. Illustrative examples of drugs for the treatment of neurogenic bladder include analgesics or anesthetics such as lidocaine, bupivacaine, mepivacaine, prilocaine, articaine and ropivacaine; anticholinergics; antimuscarinic agents such as oxybutynin or propiverine; a vanilloid such as capsaicin or resiniferatoxin; antimuscarinic agents such as agents that act on the muscarinic acetylcholine receptor (mAChRs); antispasmodics containing GABA-B receptor agonists (GABA _B ) such as baclofen; butolotoxins; capsaicins; alpha-adrenergic antagonists; anticonvulsants; a serotonin reuptake inhibitor such as amitriptyline; and nerve growth factor antagonists. In various embodiments, the drug may be an agent that affects bladder afferent stimuli or an agent that affects efferent cholinergic transmission, as described in Ritz et al., Spinal Cord 42:267-72 (2004 ).

[00092] Drugs for the treatment of neurogenic bladder can be classified into one of two general types: for the treatment of spastic neurogenic bladder and for the treatment of hypotonic neurogenic bladder. In embodiments, the drug is selected from drugs that are known to treat incontinence caused by neurological detrusor overactivity and/or detrusor with poor compatibility. Examples include drugs for bladder relaxation (eg, oxybutynin (an antimuscarinic agent with a marked muscle-relaxing effect and local anesthetic effect), propiverine, ipratropium, tiotropium, trospium, terodiline, tolterodine, propanteline, oxyphencyclimine, flavoxate, and tricyclic antidepressants; drugs for blocking bladder and urethral nerve excitation (eg, vinyloids (capsaicin, resiniferatoxin), butolotoxin A); or drugs that modulate detrusor contraction force, voiding reflex, detrusor-sphincter dyssynergy (eg, GABA-B receptor agonists (GABA _B ) (baclofen), benzodiazepines).In other embodiments, the drug is selected from drugs that are known for the treatment of incontinence due to neurological sphincter dyssynergy.Examples include alpha-adrenergic agonists, estrogens, beta-adrenergic agonists, tricyclic antidepressants ssants (imipramine, amitriptyline). In yet other embodiments, the drug is selected from drugs that are known to facilitate bladder emptying (eg, alpha-adrenergic (phentolamine) or cholinergic antagonists). In still other embodiments, the drug is selected from anticholinergic drugs (e.g., diclocymine), calcium channel blockers (e.g., verapamil), tropane alkaloids (e.g., atropine, scopolamine), nociceptin/orphanin FQ, and bethanechol (e.g., muscarinic m3 agonist, choline ether).

[00093] In specific embodiments, the functional agents or excipients comprise osmotic agents, drug dissolution agents, drug stabilization agents, penetration agents, or combinations thereof. In particular, functional agents or excipients may be suitable for facilitating release in vivo or for delivering a drug to an implant site. For example, the drug may be a low solubility drug and the functional agent may be an osmotic agent such as urea. After dissolution, the osmotic agent can facilitate the release of the drug from the case through the fluid flow caused by the osmotic pressure. Other examples of functional agents or excipients that may be used include cyclodextrins, glycerol, polyethylene glycol, citrates, acetates, phosphates, ascorbic acid, and sodium sulfite.

[00094] In embodiments, the first block or first blocks respectively contains or contain a high mass fraction of the drug, and the second block or second blocks respectively contain or contain a high mass fraction of a functional agent or excipient. For example, the first block may contain at least 50% drug by weight, at least 60% drug by weight, at least 75% drug by weight, from about 60 to about 99% drug by weight, or from about 75 to about 95% drug by weight. The second block may contain at least 80% functional agent by weight, at least 85% functional agent by weight, at least 90% functional agent by weight, from about 80 to about 99% functional agent by weight, or from about 85 to approximately 95% functional agent by weight. The remaining blocks may contain excipients such as pharmaceutical lubricants, stabilizing agents or binding agents such as oil-based lubricants, polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP). The excipients may also contain a release delay agent. For example, a release delay agent may be provided in the drug block part, in the functional agent block part, or both, to further control drug release.

[00095] In a specific embodiment, the first block contains at least 75% gemcitabine HCl by weight and the second block contains at least 85% urea by weight. For example, the first block may contain about 80% gemcitabine HCl by weight, and the second block may contain about 90% urea by weight.

[00096] In one embodiment, the housing is water-permeable, the first block contains a first tablet that contains a drug with low solubility, and the second block contains a second tablet that contains an osmotic agent that facilitates the release of the drug from the housing due to osmotic pressure. In one embodiment, the drug is gemcitabine and the osmotic agent is urea.

[00097] The device may be inserted into a body cavity or into a patient's cavity. Upon implantation, the device may release one or more drugs for the treatment of one or more conditions, locally to one or more tissues at the deployment site, or zonal to other tissues distant from the deployment site, or both. The release can be managed over an extended period of time. The device may then be removed, resorbed, excreted, or a combination thereof.

[00098] In particular embodiments, a device is administered to a patient by passing the device through a deployment tool and releasing the device from the body deployment tool. The deployment tool may be any device suitable for the cavity, such as a catheter, urethral catheter, cystoscope, or combination thereof, that is commercially available or specially adapted to deploy the present device. In specific embodiments, the device is implanted in the bladder. The device is then held in the bladder due to the presence of the retention feature, for example by being molded to be held or secured in the bladder.

[00099] The device can be deployed during an independent procedure or in combination with another urological or other procedure or operation before, during or after another procedure. The device may release one or more drugs that are delivered to local and/or local tissues for treatment or for preoperative and/or postoperative prophylaxis.

[000100] After deployment in vivo (in vivo), the device releases a drug. Release can occur, as described above, by an osmotic pressure gradient between the outside and inside of the device, with the drug passing through one or more orifices or permeable pores in the device under the influence of osmotic pressure. Release may also occur by diffusion, with the drug passing through one or more orifices or permeable pores in the device and/or through a drug-permeable wall due to a drug concentration gradient between the exterior and interior of the device. A combination of these release patterns within a single device is possible, and in some embodiments it is preferred in order to achieve a complete drug release profile that is difficult to achieve with any of the modes alone.

[000101] Upon insertion of the device into a patient, water or an aqueous body fluid from the implant site may enter the device, such as through a permeable wall or a passage in the device wall, to dissolve the functional agent or excipient and drug. For example, the functional agent or drug may be dissolved after contact with urine in cases in which the device is implanted in the bladder. The functional agent may be a dissolving agent to help dissolve the drug.

[000102] In particular embodiments, the release of at least two payloads (i.e., one payload of drug and one payload of excipient and/or functional agent) may occur according to different release profiles, including profiles that exhibit different initial release offensives such as immediate and delayed releases; profiles that show different release lengths, such as quick release and extended release; and profiles that exhibit different release rates, such as a zero order release rate or other rate. Continuous and extended release can thus be facilitated according to the required profile. For example, the device may release a useful mass of the functional agent relatively quickly, and the device may more continuously release the effective mass of the drug.

[000103] The device can provide an extended, continuous, intermittent, or intermittent release of a desired amount of drug over a desired predetermined period of time. In various embodiments, the device may deliver the required dose of drug over an extended period of time, such as 12 hours, 24 hours, 5 days, 7 days, 10 days, 14 days, or 20 days, 25 days, 30 days, 45 days, 60 days or 90 days or more. The rate of delivery and dosage of the drug may be selected depending on the drug to be delivered and the disease and health condition to be treated. In embodiments, the device is configured to release an effective treatment amount of a drug over a period of time from 1 day to 30 days, for example, from 2 days to 30 days, from 1 day to 21 days, from 1 day to 14 days, from 2 days up to 14 days or from 5 days to 7 days, etc. In particular embodiments, the drug is drug released from the device at a zero order rate over a time period of 1 day to 30 days, such as 2 days to 14 days or 3 days to 7 days.

[000104] Therefore, the device can be removed from the body, for example in cases where the device is made non-resorbable, or it must be removed in some other way. Holding devices for this purpose are known in the art or can be custom made. The device can also be completely or partially self-absorbable, so that it does not need to be removed, since the entire device is completely resorbed or substantially destroyed when pushed out of the bladder during urination, as described, for example, in US patent application publication No. 2012/0089122 ( Lee et al.), which is incorporated herein by reference. The device cannot be removed or resorbed until some or most of the drug or all of the drug has been released. If necessary, a new drug-filled device can be subsequently implanted during or after the same procedure as retrieval.

[000105] In one embodiment, an implantable device with an independent payload of drug is fully deployed in the bladder to provide local, sustained delivery of at least one drug in an effective amount to a specific location in the bladder. After the device is deployed in vivo (in vivo), at least a portion of the payload of drug is substantially continuously released from said device onto the urothelium and, if possible, adjacent tissues over an extended period of time in an amount effective to treat the patient or to improve function. his bladder. In a preferred embodiment, the device resides in the bladder releasing the drug for a predetermined period of time, such as two weeks, three weeks, four weeks, a month or more. In such cases, the device can be used to treat interstitial cystitis, chemical cystitis, radiation cystitis, hemorrhagic cystitis caused by radiation and chemotherapy, ketamine-induced cystitis (or ketamine bladder syndrome), pelvic pain, overactive bladder syndrome, bladder cancer. , neurogenic bladder, neurogenic bladder sphincter dysfunction, or bladder sphincter dysfunction of a different non-neurogenic nature, infection, postoperative pain, or other diseases, disorders, and conditions that are treated with drugs delivered to the bladder. The device can deliver drugs that improve bladder function, such as bladder capacity, compliance, and/or unrestrained contractions, resulting in less pain and discomfort in the bladder or other nearby areas, or that have other effects or effects. combination.

[000106] In some embodiments, a drug delivery device is deployed in the patient's bladder for zonal drug delivery to one or more nearby genitourinary sites. The device can locally release the drug into the bladder and zonal to other sites adjacent to the bladder. The bladder-deployable device may also deliver a therapeutically effective amount of one or more drugs to other genitourinary sites within the body, such as other sites within the urological or reproductive system of the body, containing one or both kidneys, urethra, one or both ureters, penis , testicles, one or both seminal vesicles, one or both vas deferens, one or both ejaculatory ducts, prostate, vagina, uterus, one or both ovaries, one or both fallopian tubes, among others, or a combination thereof. For example, an intravesical drug delivery device may be used in the treatment of kidney stones or kidney fibrosis, erectile dysfunction, among other diseases, disorders and conditions. Such delivery may provide an alternative to systemic administration, which may lead to undesirable side effects or to insufficient drug bioavailability.

[000107] The present invention may be further understood with reference to the following non-limiting examples. Unless otherwise indicated, all percentages are weight percentages.

[000108] Example 1: Single Device Versus Multi Device

[000109] Models of the drug delivery device were made using silicone tubes having an internal diameter of 2.64 mm.

[000110] The one-piece device is made in accordance with the embodiment of the device shown in FIG. 1. The tube was loaded with a plurality of tablets containing 17.7% gemcitabine hydrochloride (164 mg pure base equivalent (FBE)), 73.6% urea, 7.8% pharmaceutical lubricant based on LUBRITABA® oil (sold to the market by JRS PHARMA , Rosenberg, Germany) and 0.9% polyvinylpyrrolidone (PVP) K29-32 (available commercially under the brand name PLASDONE® from International Specialty Products, New Jersey). The tablets were made with a diameter substantially the same as the inner diameter of the tube and were loaded into the tube to form a sequential pattern. The tablets filled a length of 15.2 cm. The device contained a separation type outlet with a length of 5 mm.

[000111] The multi-unit device is also configured in accordance with the device embodiment shown in FIG. 2. The tube was loaded with multiple drug tablets containing 80.0% gemcitabine HCl, 13.3% urea, 4.2% polyvinylpyrrolidone (PVP) K29-32, and 2.5% polyethylene glycol (PEG) 8000. the agent filled a length of 2.8 cm and were sequentially located close to the outlet of the separation type with a length of 5 mm. The tube was also loaded with a plurality of functional agent tablets containing 90.0% urea and 10.0% lubritab. The functional agent tablets filled a 12.0 cm length of tube.

[000112] The total composition of the multi-unit device was 18.9% gemcitabine HCl, 71.8% urea, 7.7% lubritab, 1.0% polyvinylpyrrolidone (PVP) K29-32 and 0.6% polyethylene glycol (PEG) 8000, which was comparable to the overall composition of a single-block device. Specifically, the single-unit device contained 164.0 mg gemcitabine pure base equivalent (FBE) and the multi-unit device contained 163.8 mg gemcitabine pure base equivalent (FBE).

[000113] In vitro drug release profiles were measured for single and multiple devices in water. In FIG. 9 and 10 show percent drug release and release rate (measured in mg gemcitabine pure base equivalent (FBE) per day) versus time, respectively. Overall, the multi-unit device performed better than the single-unit device, releasing a higher percentage of drug and maintaining a higher drug release rate for a longer period of time. According to FIG. 9, the multi-unit device released more than 90% of its net drug weight in a seven-day time period, and the single-unit device released less than 80% of its net drug weight in the same time period. According to FIG. 10, the multi-unit device also had a "flatter" release profile in which the drug release rate remained between 2 and 4 days. A flat profile is essential for long-term drug release. For example, a multi-unit device performs better than a single-unit device in continuous long-term drug release over a period of 5 to 7 days.

[000114] Example 2: Laser-Shaped Exhaust Versus Separation-Type Exhaust in Multiunit Devices

[000115] A multi-block device having a separation type outlet is made in accordance with the embodiment of the device shown in FIG. 2. The outlet had a length of 5 mm and an inner diameter of 0.3 mm. The separation hole was located at one end of the tube.

[000116] A multi-unit device having a laser-shaped outlet is made in accordance with the embodiment of the device shown in FIG. 3. The outlet had an inner diameter of 0.150 mm and was located on the wall of the device case.

[000117] Each tube was filled with a plurality of drug tablets and a plurality of functional agent tablets. The functional agent tablets contained 90.0% urea and 10.0% lubritab and filled a 6.0 cm tube length. The drug tablets contained 80.0% gemcitabine HCl, 13.3% urea, 4.2% polyvinylpyrrolidone ( PVP) K29-32 and 2.5% polyethylene glycol (PEG) 8000 and filled a length of 2.5 cm tube. 140.5 mg gemcitabine pure base equivalent (FBE)).

[000118] Referring to FIG. 3, in the laser-shaped hole device 300, 3 cm functional agent tablets 310 were positioned on each side of 2.5 cm drug tablets 302 such that the drug tablets 302 were centered around the laser-shaped hole 306. Referring to FIG. . 2, in the separation opening device 200, 2.5 cm of drug tablets 202 were located adjacent to the separation opening 206, and 6.0 cm of functional agent tablets 210 were adjacent to the drug tablets 202.

[000119] In vitro drug release profiles were measured for the laser-shaped hole device and the water separation hole device. In FIG. 11 and 12 show percent drug release and release rate (measured in mg gemcitabine pure base equivalent (FBE) per day) versus time, respectively. In general, both devices showed similar release profiles, releasing up to about 70% of the effective weight of the drug in 7 days at a rate of essentially zero order. The release rate profiles of the devices are also similar, with a flat spot at approximately 20 mg pure base equivalent (FBE) release per day between days 1-4.

[000120] Example 3: Powder drug multi-unit devices versus tablet drug multi-unit devices

[000121] A multi-unit device having tablets with a drug and a functional agent is made in accordance with the embodiment of the device shown in FIG. 2. The functional agent tablets contained 90.0% urea and 10.0% lubritab and filled a 6.0 cm tube length. The drug tablets contained 80.0% gemcitabine HCl, 13.3% urea, 4.2% polyvinylpyrrolidone (PVP) K29-32 and 2.5% polyethylene glycol (PEG) 8000, and filled a 1.5 cm tube length. The tablet drug device contained 123.4 mg gemcitabine pure base equivalent (FBE).

[000122] A multi-unit device having functional agent tablets and a powder drug block is made in accordance with the embodiment of the device shown in FIG. 4. The functional agent tablets 410 contained 80% urea and 20% lubritab and filled a tube length of 7.8 cm. The drug powder block 402 contained 80% gemcitabine HCl and 20% urea powder and filled a tube length of 3.4 see Powder drug device contained 124.4 mg gemcitabine pure base equivalent (FBE).

[000123] Each device included a separation type outlet having an inner diameter of 0.300 mm and a length of 5.0 mm.

[000124] In vitro drug release profiles were measured for the laser-shaped hole device and the water separation hole device. In FIG. 13 and 14 show percent drug release and release rate (measured in mg gemcitabine FBE per day) versus time, respectively. In general, both devices showed similar release profiles, releasing up to about 85% of the effective weight of the drug in 7 days at a rate of essentially zero order. The release rate profiles of the devices are also similar, with a flat area above 20 mg pure base equivalent (FBE) release per day between days 1-4.

[000125] According to the examples above, multi-unit drug delivery devices provide improved short-term and long-term drug release profiles compared to comparable single-unit devices. These devices advantageously allow for a controlled, sustained release of the drug, for example a zero order release of 5-7 days. In addition, these devices provide a means for delivering low solubility drugs to a patient via osmotic release devices. This is particularly useful for drugs that are difficult to convert to higher solubility forms. Thus, these devices are capable of delivering a variety of different drugs through different release mechanisms and release kinetic profiles, and provide improved control of drug release in vivo, such as from a device deployed in the bladder.

[000126] Example 4: Effect of Wall Thickness and Hardness of Silicone Tubing Body on Device Release

[000127] A multi-unit device having drug and functional agent tablets was made in accordance with the device embodiment shown in FIG. 17. The functional agent tablets were osmotic tablets. The mass and length of the osmotic tablet were approximately 400 mg and 6 cm, respectively, and the mass and length of the drug tablet were approximately 150 mg and 2 cm, respectively. The composition of the drug tablet (gemcitabine) was 85.5% gemcitabine HCl, 5 % urea, 4.5% polyvinylpyrrolidone (PVP) K30, 2.5% neusilin and 2.5% magnesium stearate. The composition of the osmotic tablet was 90% urea and 10% lubritab. All tablets were made by a direct powder compression process.

[000128] In this example, four different types of extruded silicone hollow bodies were used: 1) 2.64 mm inner diameter, 0.13 mm wall, 65 Shore A hardness (MED-4765, Co. NuSil Technology LLC"); 2) inner diameter 2.64 mm, wall 0.1 mm, hardness 80 Shore A (MED-4780, NuSil Technology LLC); 3) inner diameter 2.64 mm, wall 0.2 mm, hardness 50 Shore A (MED-4750, NuSil Technology LLC); and 4) 264 mm ID, 0.4 mm wall, 25 Shore A hardness (MED-4720, NuSil Technology LLC).

[000129] In each device shown in FIG. 17, one end of the tubing was sealed with MED3-4213-1 silicone adhesive (NuSil Technology LLC) and the other end contained a retaining plug made of ethylene vinyl acetate (EVA) surfacing (FBK medical tubing) containing Elvax 760, an ethylene vinyl acetate (EVA) copolymer. The ethylene vinyl acetate plug had an approximate outer diameter of 2.74 mm and a length of 5 mm, and a 30-60° cut was made at one end of the plug. The empty space created by the cutout surface and the silicone tube was filled with silicone adhesive as shown in FIG. 17, which served as a stopper to prevent the plug from separating when osmotic pressure was applied to the silicone tube. Under laboratory (in vitro) release was performed in deionized water at 37°C and the results are shown in FIG. 19. The sample size for each group was 2, and error bars indicate the standard deviation (SD) around the mean. Some error bars are not visible if they are less than symbols. As used in the graph, "O" refers to the osmotic tablet and "A" refers to the active pharmaceutical ingredient, i.e. drug, tablet.

[000130] In particular, in FIG. 19 shows the amount of drug released over time from a device having different body wall thicknesses and hardnesses. The release characteristics of gemcitabine depended on the wall thickness and hardness of the silicone tube body. These findings indicate that the size of the housing, including wall thickness, strength, and elasticity of the housing material, can be selected based on the volume of drug and functional agent formulations to be contained, as well as the desired drug delivery rate from the tube.

[000131] Example 5 Effect of Wall Thickness and Hardness of Silicone Tubing Body on Device Release

[000132] Another series of experiments was performed using the device configuration shown in FIG. 17. Three different silicone hollow bodies were used in this example: 1) 2.64 mm ID, 0.2 mm wall, 50 Shore A hardness (MED-4750, NuSil Technology LLC »); 2) inner diameter 2.64 mm, wall 0.2 mm, hardness 70 Shore A (MED-4770, NuSil Technology LLC); and 3) 2.64 mm ID, 0.4 mm wall, 25 Shore A hardness (MED-4720, NuSil Technology LLC).

[000133] The tablets were placed next to each other in the reservoir as shown in FIG. 17. The mass and length of the osmotic tablet were approximately 700 mg and 11 cm, respectively, and the mass and length of the drug tablet were approximately 300 mg and 4.5 cm, respectively. The composition of the drug tablet (gemcitabine) contained 85.5% gemcitabine HCl, 5% urea, 4.5% polyvinylpyrrolidone (PVP) K30, 2.5% neusilin and 2.5% magnesium stearate. The composition of the osmotic tablet contained 90% urea and 10% lubritab. All tablets were made by a direct powder compression process. Under laboratory (in vitro) release was performed in deionized water at 37°C and the results are shown in FIG. 20. The sample size for each group was 2 and the error bars indicate the standard deviation (SD) around the mean. Some error bars are not visible if they are less than symbols. As used in the graph, "O" refers to the osmotic tablet and "A" refers to the active pharmaceutical ingredient, i.e. to a drug, a tablet.

[000134] In particular, in FIG. 20 shows the amount of drug released over time from a device having different housing wall thicknesses and hardnesses. The release characteristics of gemcitabine depended on the wall thickness and hardness of the silicone tube body. These results indicate that the size of the body, including wall thickness, length and strength, and elasticity of the body material, can be selected based on the volume of drug and functional agent formulations to be contained, as well as on the required delivery rate. medication from the tube.

[000135] Example 6: Influence of the length of the area of the impermeable coating of the silicone body of the tubing on the release of drug from the device

[000136] A multi-unit device having drug and functional agent tablets was made in accordance with the device embodiment shown in FIG. 18. Unlike previous configurations, parylene C (waterproof coating) was partially applied to an extruded silicone tube having an inner diameter of 2.64 mm, a wall of 0.2 mm and a hardness of 50 Shore A) (MED -4750, NuSil Technology LLC). A hole with a diameter of 0.3 mm was made at one end of the tube, and the other end was sealed with silicone adhesive MED3-4213-1. Three different silicone tube body configurations were tested: 1) osmotic tablet weight/length: 700 mg/11 cm, drug tablet weight/length: 320 mg/4.5 cm, parylene coated area length: 6.5 cm; 2) osmotic tablet weight/length: 700 mg/11 cm, drug tablet weight/length: 320 mg/4.5 cm, parylene coated area length: 11 cm; and 3) osmotic tablet weight/length: 400 mg/6 cm, drug tablet weight/length: 150 mg/2 cm, parylene coated area length: 4 cm.

[000137] In vitro release was performed in DI water at 37°C and the results are shown in FIG. 21. The sample size for each group was 2 and the error bars indicate the standard deviation (SD) around the mean. Some error bars are not visible if they are less than symbols. As used in the graph, "O" refers to the osmotic tablet and "A" refers to the active pharmaceutical ingredient, i.e. medicinal substance, tablet.

[000138] In particular, in FIG. 21 shows the amount of drug released over time from a device having different lengths of waterproof coverage areas. The release characteristics of gemcitabine depended on the length of the parylene-coated region relative to the length of the osmotic tablet and drug tablet regions. These results indicate that the length of the watertight region can be selected based on the volume of drug and functional agent formulations to be contained therein, as well as the desired drug delivery rate from the tube. In addition, a case cover may be useful when the material of the case is drug-permeable and when osmotic release is required.

[000139] The publications disclosed in this application, as well as the materials for which they are disclosed, are specifically incorporated into this application by reference. Modifications and changes to the methods and devices described in this application will become apparent to those skilled in the art from the above detailed description. Such modifications and changes are within the scope of the appended claims.

Claims (32)

1. A device for intravesical drug delivery, comprising: a first housing portion loaded with a medicament formulation that contains a medicament, and the second part of the body, loaded with filler, wherein said device is configured to release the drug according to the first release profile and to release the excipient according to a second release profile different from the first release profile. 2. The device according to claim. 1, in which it is possible to release the medicinal product from the first part of the body through an opening made in this first part of the body, mainly by means of osmotic pressure. 3. The device according to claim 2, in which it is possible to release the filler from the second part of the body by diffusion. 4. The device of claim. 1, which provides the possibility of discharging the drug from the first part of the body by diffusion through the drug-permeable wall in the first part of the body. 5. The device according to claim 4, in which it is possible to discharge the filler from the second part of the body through an opening made in this second part of the body, mainly by means of osmotic pressure. 6. The device according to any one of paragraphs. 1-5, wherein the filler contains a dissolving agent, a stabilizing agent, or a permeability agent. 7. The device according to any one of paragraphs. 1-5, wherein the drug formulation is in the form of tablets and the excipient is in the form of tablets. 8. A method of administering a drug to a patient, including: introduction to the patient of the device according to any one of paragraphs. 1-7; And release of the drug from the injected device. 9. The method of claim 8, wherein the device is inserted into the patient's bladder. 10. The method of claim 8 or 9, wherein after insertion of the device into the patient, water or other aqueous body fluids enter the housing and dissolve the drug and the functional agent or excipient. 11. The method of claim 10, wherein the drug is released from the device at a zero order rate over a period of 2 to 14 days. 12. A device for intravesical drug delivery, comprising: a housing that contains a permeable elastomeric tube containing (i) a cavity defining a reservoir, and (ii) a drug release port in communication with the reservoir; first tablets which contain a drug, the first tablets being contained within the reservoir in first positions; And second tablets which contain an osmotic agent, wherein the second tablets are contained within the reservoir in second positions that differ from the first positions and are in fluid communication with them, wherein said device is elastically deformable between a straight shape suitable for insertion through a patient's urethra into the patient's bladder and a holding form suitable for holding said device within the bladder, and wherein said device is configured, after intravesical administration, to dissolve the first and second tablets with urine diffusing into the reservoir and release the dissolved drug through the drug outlet by means of the osmotic pressure generated in the reservoir. 13. The device of claim 12 wherein the drug contains gemcitabine and the osmotic agent contains urea. 14. The device according to claim 12 or 13, in which: the second tablets are positioned within opposite end regions of the reservoir, the first tablets are positioned within the middle region of the reservoir between the second tablets, and the drug release port is positioned in the side wall of the elastomeric tube adjacent the first tablets. 15. A device for intravesical drug delivery, comprising: a housing that includes a water-permeable silicone tube comprising (i) a cavity defining a cylindrical reservoir, and (ii) a drug outlet port in a side wall of the silicone tube, the drug outlet port communicating with the cylindrical reservoir; drug tablets which contain at least 75% by weight of gemcitabine; And tablets with an osmotic agent which contain at least 85% by weight of urea, where tablets with an osmotic agent are located inside opposite end regions of the cylindrical reservoir, and tablets with a drug are located inside the middle region of the cylindrical reservoir between the tablets with an osmotic agent. 16. The intravesical drug delivery device of claim 15, wherein the drug tablets are centered around a drug release port. 17. An intravesical drug delivery device according to claim 15 or 16, wherein said device is configured, after intravesical administration, to dissolve the first and second tablets with urine diffusing into the reservoir and release gemcitabine through the drug release port by osmotic pressure, created in the tank.

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